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Originally published In Press as doi:10.1074/jbc.M205535200 on August 12, 2002

J. Biol. Chem., Vol. 277, Issue 42, 39666-39672, October 18, 2002
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CIN85 Participates in Cbl-b-mediated Down-regulation of Receptor Tyrosine Kinases*

Iwona SzymkiewiczDagger , Katarzyna KowanetzDagger , Philippe SoubeyranDagger §, Ana DinarinaDagger , Stanley Lipkowitz, and Ivan DikicDagger ||

From the Dagger  Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden and the  Cancer Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889

The Cbl family of ubiquitin ligases in mammals contains three members, Cbl, Cbl-b, and Cbl-3, that are involved in down-regulation of receptor tyrosine kinases (RTKs) by mediating receptor ubiquitination and degradation. More recently, a novel pathway has been identified whereby Cbl promotes internalization of EGF receptor via a CIN85/endophilin pathway that is functionally separable from the ubiquitin ligase activity of Cbl (1). Here we show that Cbl-b, but not Cbl-3, utilize the same mechanism to down-regulate multiple RTKs. CIN85 was shown to bind to the minimal binding domain identified in the carboxyl terminus of Cbl-b. Ligand-induced phosphorylation of Cbl-b further increased their interactions and led to a rapid and sustained recruitment of CIN85 in the complex with EGF or PDGF receptors. Inhibition of binding between CIN85 and Cbl-b was sufficient to impair Cbl-b-mediated internalization of EGF receptors, while being dispensable for Cbl-b-directed polyubiquitination of EGF receptors. Moreover, CIN85 and Cbl/Cbl-b were constitutively associated with activated PDGF, EGF, or c-Kit receptors in several tumor cell lines. Our data reveal a common pathway utilized by Cbl and Cbl-b that may have an important and redundant function in negative regulation of ligand-activated as well as oncogenically activated RTKs in vivo.

* This work was supported in part by grants from the Swedish Strategic Funds (to I.D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported in part by a Marie Curie Fellowship of the European Community program.

|| Research fellow of the Boehringer Ingelheim Fonds. To whom correspondence should be addressed: Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden. Tel.: 46-18-160403; Fax: 46-18-160420; E-mail: Ivan.Dikic@LICR.uu.se.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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